JAK-STAT Signaling: From Interferons to Cytokines

Abstract

50 years ago Isaacs and Lindenmann (1) first described interferons (IFNs) 2 as founding members of the cytokine family. Over the next 25 years, these and several other four-helix bundle cytokines were characterized. The subsequent 25 years witnessed an exponential growth in number of four-helix bundle cytokines and their corresponding receptors.The early availability of recombinant IFNs afforded an opportunity to investigate how cytokines induce gene expression, culminating in the identification of the JAK-STAT signaling paradigm (see Fig. 1). Subsequent studies identified 7 STATs and 4 JAKs, providing important insight into how the ϳ50 members of the four-helix bundle cytokine family transduce their potent biological responses. This review will briefly summarize this signaling paradigm (reviewed in Refs. 2-5) and then focus on STAT-dependent transcription.

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

“…In the current study, we show that the numbers of circulating fibrocytes and the activation state were also enhanced early in the CAIA model. Phosphorylated STAT-5 can be activated in response to multiple cytokines, including stem cell factor, interleukin-2 (IL-2), IL-3, IL-5, IL-7, and granulocyte-macrophage colonystimulating factor (GM-CSF), as well as multiple growth factors including insulin, erythropoietin, and thrombopoietin (16). It is unclear why only a subset of circulating fibrocytes exhibit phosphorylation of STAT-5.…”

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

“…The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes.…”

“…STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al 2003;Mertens et al 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes.…”

Intronless and intron-containing type I IFN genes coexist in amphibian Xenopus tropicalis : Insights into the origin and evolution of type I IFNs in vertebrates

“…When they bind the transmembrane heterodimer of IFNAR1 and IFNAR2, the IFNAR1-associated tyrosine kinase 2 (TYK2) and the IFNAR2-associated Janus kinase 1 (JAK1) are activated, and tyrosine residues in receptors are phosphorylated (O'Shea and Plenge, 2012). These phosphorylated tyrosine residues form docking sites for signal transducer and activator of transcription 1 (STAT1) and STAT2, which are also phosphorylated, dissociated from the receptors, and become dimerized and translocated to the nucleus, where they are assembled with IFN regulatory factor 9 (IRF-9) to form a trimolecular complex called IFNstimulated gene (ISG) factor 3 (ISGF3) (Schindler et al, 2007;Stark and Darnell, 2012), which can then bind to IFN-stimulated response elements (ISREs), thus activating the transcription of several hundred ISGs (Schoggins et al, 2011).…”